Triazolobenzazepines

ABSTRACT

There is presented triazolobenzazepines of the formula ##STR1## wherein R 1  is hydrogen or lower alkyl and X and Y are hydrogen or halogen 
     and the pharmaceutically acceptable salts thereof. 
     Also disclosed are novel processes and intermediates leading to the triazolobenzazepines. 
     The triazolobenzazepines are useful compounds having anxiolytic, sedative, muscle relaxant and anticonvulsant activity.

This is a division, of application Ser. No. 99,109 filed Nov. 30, 1979,now U.S. Pat. No. 4,243,589.

DESCRIPTION OF THE INVENTION

The present invention relates to triazolobenzazepines of the formula##STR2## wherein R₁ is hydrogen or lower alkyl and X and Y are hydrogenor halogen

and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds are those wherein X is chloro, Y ishydrogen, chloro or fluoro and R₁ is hydrogen or methyl with the2-position as preferred for the methyl substituent along with the3-position.

As used herein, the term "lower alkyl" means a branched or straightchain hydrocarbon radical of C₁ to C₇ length with C₁ to C₄ as preferred,e.g., methyl, ethyl, isopropyl, butyl, etc.

As used herein, the term "halogen" means all four forms thereof, i.e.,chloro, bromo, iodo and fluoro.

The following set forth the reaction scheme utilized to produce thenovel end products: ##STR3## wherein X and Y are as above ##STR4##wherein X and Y are as above ##STR5## wherein R₁, X and Y are as above

I→II and IIA

The compound of formula I is a previously disclosed compound, see U.S.patent application Ser. No. 10,118, and may be produced following theteaching set forth in Examples 17 to 26. The compound of formula I maybe reacted with an alkali metal azide, such as, sodium or potassiumazide and a lower alkyl carboxylic acid, such as, acetic or propionicacid, in a polar aprotic solvent, such as, dimethylsulfoxide ordimethylformamide. The reaction temperature may be varied from aboutroom temperature to about 110° C. with the particular preferredtemperature chosen dependent on the substitution pattern of the moietiesX and Y. The byproduct IIA is thereafter isolated and discarded.

II→III

The compound of formula II is thereafter reacted with an aqueoussolution of a lower alkyl amine, e.g., methyl amine. A C₁ to C₄ alcoholis utilized as the solvent with ethanol as preferred. The reaction ismost preferably carried out at about room temperature. The final productis isolated thereafter by utilizing well-known filtration techniques.The first formed open amine is not isolated but undergoes spontaneousring closure to the first product III.

An alternate method to produce the compound of formula III consists ofthe reaction of the compound of formula II with hydrazine in an inertsolvent, such as, ethanol, a mixture of ethanol and chloroform,tetrahydrofuran or aqueous ethanol. The reaction temperature may varyfrom about room temperature to about 100° C. with reflux temperature ofthe selected solvent as preferred. The product is extracted with dilutemineral acid and thereafter recovered and neutralized.

A third method which may be utilized to produce the compound of formulaIII consists of a base followed by acid hydrolysis of the compound offormula II. For the acid part of the hydrolysis, a 30% solution of amineral acid such as, hydrochloric, hydrobromic, sulfuric or phosphoricacid may be utilized. The reaction is run at or about refluxtemperature. For a base part of the hydrolysis, an alkali metalhydroxide such as potassium or sodium hydroxide is utilized. Inertorganic solvents, such as those set forth above may be utilized tosolubilize the ingredients. The reaction is run at or near refluxtemperature of the selected solvent.

III→IV

The compound of formula III is thereafter reacted with any conventionalnitrating agent, for example, an alkali metal nitrate, such as, sodiumor potassium nitrate in sulfuric acid. The reaction is carried out fromabout 0° C. to about room temperature with 0° C. as preferred.

V→VI

The compound of formula V is reduced by utilizing a metal hydridereducing agent such as sodium borohydride in an alcoholic solvent, suchas, ethanol or methanol or lithium aluminum hydride in an etherealsolvent, such as, tetrahydrofuran or dioxane. The reaction temperaturemay range from about -10° C. to about room temperature with about 0° C.as preferred.

VI→VII

The compound of formula VI is thereafter reacted with a combination ofpalladium chloride, cuprous iodide, triphenylphosphine andpropargylphthalimide in a solvent, such as, methylene chloride ordimethylformamide utilizing as a base a di- or tri- alkylamine, e.g.,diethylamine, triethylamine. The above reaction may be run at from about0° C. to about 40° C. with about room temperature as preferred.

VII→VIII

A compound of formula VII is thereafter reacted with an alkali metalazide and a lower alkyl carboxylic acid in the pressure of an inertpolar aprotic solvent, such as, dimethylsulfoxide and dimethylformamide.The reaction temperature may be varied from about 60° C. to about 100°C. with about 90° C. as preferred.

VIII→II

The benzhydrol compound of formula VIII is thereafter oxidized utilizingan oxidizing agent such as the Jones or Collins reagent in an inertorganic solvent, such as, methylene chloride or acetone. The reactiontemperature may be varied from about -10° C. to about room temperaturewith about 0° C. preferred.

X→XI

The compound of formula X can be prepared following methods taught inU.S. patent application Ser. No. 10,118 filed on Feb. 7, 1979 toTrybulski which is incorporated by reference herein. The compound isreacted with abenzoylating agent, such as, benzoyl chloride in pyridineor benzoic acid anhydride in pyridine. Solvents for the reaction includepyridine or methylene chloride. The reaction temperature may vary fromabout 0° C. to about room temperature with room temperature aspreferred.

XI→XII

The compound of formula XI is thereafter reacted with an alkali metalazide, such as, sodium or potassium azide in the presence of an inertpolar aprotic solvent such as dimethylformamide or dimethylsulfoxide.The reaction may be run at from about room temperature to about 100° C.with about 80° C. as preferred.

XII→III

The compound of formula XII is thereafter hydrogenated in the presenceof a transition metal catalyst, such as Raney nickel or Platinum oxideand, if desired, in the presence of a mineral acid, such as,hydrochloric acid. The reaction takes place at about room temperatureand at a pressure which may be varied from atmospheric pressure to about40 psi with atmospheric pressure preferred.

III→XIII

The compound of formula III is thereafter treated with an alkali metalhydroxide, e.g., sodium or potassium hydroxide in a C₁ to C₆ alcohol,preferably a C₁ to C₄ alcohol. Subsequently the resultant mixture isreacted with a suitable alkylating agent such as a dialkyl sulfate, e.g.dimethylsulfate, an alkyl halide, e.g. methyl chloride or an alkyltosylate. The reaction may be carried out from about 0° C. to about roomtemperature with about room temperature preferred.

The major product in the alkylation was assigned to the 2-positionisomer. A minor product was isolated and assigned to the 3-positionisomer.

The expression "pharmaceutically acceptable salts" is used to includeboth inorganic and organic pharmaceutically acceptable strong acids,such as, sulfuric acid, hydrochloric acid, nitric acid, methanesulfonicacid and paratoluenesulfonic acid. Such salts can be formed quitereadily by those skilled in the art with the prior art and the nature ofthe compound to be placed in salt form in view.

The following examples are illustrative of the present invention and arenot intended to limit the scope thereof.

EXAMPLE 14-[4-Chloro-2-benzoylphenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A mixture of 20 g (0.05 mole) of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne, 15.0 g (0.23 mole) ofsodium azide and 3.0 ml (0.05 mole) of acetic acid in 300 ml of dimethylsulfoxide was heated to 90° C. for 3 days. The mixture was cooled,diluted with 1.5 L of water and 250 ml of methylene chloride. Themixture was extracted with ether and the combined ether extracts washedwith water. The ether solution was dried with anhydrous sodium sulfateand concentrated at reduced pressure to give crude end product.Recrystallization from a mixture of methylene chloride and ether gavecolorless needles, mp 134°-136° C.

EXAMPLE 24-[4-Chloro-2-(2-fluorobenzoyl)phenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A mixture of 10 g (24 mmole) of1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne, 7.5 g (115mmole) of sodium azide, 2.2 ml (36 mmole) of acetic acid and 150 ml ofdimethyl sulfoxide was heated to 50° for 48 hr. The mixture was cooled,diluted with water, and the resulting precipitate collected byfiltration to give 11.0 g of the crude mixture. Purification by columnchromatography (silica gel, 105 g; eluent methylene chloride to 5% etherin methylene chloride gradient) gave as the first major component fineprisms, mp 252°-253° C. and the title compound as the second componentas light sensitive prisms, mp 147°-148° C. (foams).

EXAMPLE 34-[4-Chloro-2-(2-chlorobenzoyl)phenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A mixture of 6.8 g (15.6 mmole) of1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne, 5.0 g (85mmole) of sodium azide, 1.0 ml (17 mmole) of acetic acid, and 75 ml ofdimethyl sulfoxide was heated to 50° C. for 48 hr. The mixture wascooled, diluted with water, and extracted with methylene chloride. Themethylene chloride solution was washed with water, dried with anhydroussodium sulfate, and concentrated at reduced pressure to give 6.5 g of ayellow foam. Purification by column chromatography (silica gel, 40 g;eluent, methylene chloride to 5% ether in methylene chloride gradient)gave colorless prisms, mp 186°-187° C.

EXAMPLE 44-[2-(2-Chlorobenzoyl)phenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A mixture of 10.0 g (25 mmole) of1-[2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne, 7.5 g (115 mmole) ofsodium azide, 1.5 ml (25 mmole) of acetic acid and 150 ml of dimethylsulfoxide was heated to 90° C. for 24 hr. The mixture was cooled,diluted with water, and extracted with methylene chloride. The methylenechloride solution was washed with water, dried with anhydrous sodiumsulfate, and concentrated at reduced pressure to give a brown oil.Trituration with a mixture of ether and petroleum ether gave creamcolored prisms, mp 105°-106° C. (foams).

EXAMPLE 5 4-[2-Benzoylphenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A mixture of 10.0 g (27.0 mmole) of1-(2-benzoylphenyl)-3-phthalimidopropyne, 7.5 g (115 mmole) of sodiumazide, 1.5 ml (25 mmole) of acetic acid, and 150 ml of dimethylsulfoxide was heated to 90° C. for 60 hr. The mixture was cooled,diluted with water, and extracted with methylene chloride. The methylenechloride solution was washed with water, dried with anhydrous sodiumsulfate, and concentrated at reduced pressure to give a brown oil.Crystallization with ether gave tan crystals. Recrystallization from amixture of ether and methylene chloride gave white prisms, mp 204°-205°C.

EXAMPLE 6 8-Chloro-6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

A mixture of 6.0 g (13.6 mmole) of4-[4-chloro-2-benzoylphenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole,50 ml of 40% aqueous methylamine, and 100 ml of 95% ethanol was stirredat room temperature for 12 hr. The solvents were removed at reducedpressure, and the residue was triturated with a 2 to 1 mixture of etherand methylene chloride. The resulting precipitate was removed byfiltration, and the filtrate was washed with water and dried withanhydrous sodium sulfate. Concentration of the ether solution at reducedpressure gave colorless prisms, mp 199°-200° C.

EXAMPLE 78-Chloro-6-(2-fluorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

The preparation of8-chloro-6-(2-fluorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepinwas conducted in the same manner as the preparation of8-chloro-6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine to give acolorless solid, mp 192°-193° C.

The methanesulfonate salt of8-chloro-6-(2-fluorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepinewas prepared by adding equimolar amounts of the above compound andmethanesulfonic acid to methanol, and isolated by precipitating the saltwith the addition of ether. Recrystallization from a mixture of methanoland ether gave the methanesulfonate salt as yellow prisms, mp 237°-238°C.

EXAMPLE 88-Chloro-6-(2-chlorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

The preparation of8-chloro-6-(2-chlorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepinewas conducted in the same manner as the preparation of8-chloro-6-phenyl-2H, 4H-[1,2,3]triazolo[4,5-d][2]benzazepine to givecolorless prisms, mp 176°-177° C.

The methanesulfonate salt of8-chloro-6-(2-chlorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepinewas prepared by adding equimolar amounts of the above compound andmethanesulfonic acid to methanol and isolated by precipitating the saltwith the addition of ether. Recrystallization from a mixture of methanoland ether gave the methanesulfonate salt as yellow prisms, mp 236°-237°C.

EXAMPLE 9 6-(2-Chlorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

The preparation of6-(2-chlorophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine wasconducted in the same manner as the preparation of8-chloro-6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine to givecolorless prisms, mp 191°-193° C.

The methanesulfonate salt of6-(2-chlorophenyl)-2H,4H-[1,2,3-triazolo[4,5-d][2]benzazepine wasprepared by adding equimolar amounts of the above compound andmethanesulfonic acid to methanol and isolated by precipitating the saltwith the addition of ether. Recrystallization from a mixture of methanoland ether gave the methanesulfonate salt as yellow needles, mp 238°-240°C.

EXAMPLE 10 6-Phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

The preparation of 6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepinewas conducted in the same manner as the preparation of8-chloro-6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine to givecolorless prisms, mp 205°-207° C.

The methanesulfonate salt of6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine was prepared byadding equimolar amounts of the above compound and methanesulfonic acidto methanol, and isolated by precipitating the salt with the addition ofether. Recrystallization from a mixture of methanol and ether gave themethanesulfonate salt as yellow prisms, mp 169°-170° C.

EXAMPLE 114-{4-Chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-5-(N-phthalimidomethyl)-2H-1,2,3-triazole

A mixture of 1.5 g (3.5 mmole) of1-{4-chloro2-[(2-fluorophenyl)hydroxymethyl]phenyl}-3-phthalimidopropyne,2.0 g (30 mmole) of sodium azide and 0.4 ml (6.6 mmole) of acetic acidin 30 ml of dimethyl sulfoxide was heated in an oil bath to 90° C. for 4days. The mixture was cooled, diluted with water and the resultingprecipitate collected by filtration to give a yellow solid. A sample ofthe yellow solid was recrystallized from ether to give off-white prisms,mp 160°-162° C.

EXAMPLE 124-[4-Chloro-2-(2-fluorobenzoyl)phenyl]-5-[N-phthalimidomethyl]-2H-1,2,3-triazole

A solution of 2.67 M Jones reagent (5 ml, 13.3. mmole) was addeddropwise to a solution of 1.0 g (2.1 mmole) of4-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-5-(N-phthalimidomethyl)-2H-1,2,3-triazolein 20 ml of acetone. The mixture was stirred at room temperature for 1hr and the excess Jones reagent was discharged by the addition ofisopropanol. The acetone solution was decanted and the acetone removedat reduced pressure. The residue was dissolved in methylene chloride,washed with water and dried over anhydrous sodium sulfate. Concentrationof the methylene chloride solution gave, after trituration of theresidue with ether, the end product, (mp 133°-135° C., foams) which wasidentical in every respect to an authentic sample.

EXAMPLE 13 6-(3-Nitrophenyl)-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

A mixture of 1.6 g (4.5 mmole) of the methanesulfonate salt of6-phenyl-2H,4H[1,2,3]triazolo[4,5-d][2]benzazepine, 8.6 g of potassiumnitrate, and 20 ml of sulfuric acid was stirred at 0° C. for 3.5 hr. Themixture was poured over ice, basified with ammonium hydroxide andextracted with methylene chloride. The methylene chloride solution wasdried with anhydrous sodium sulfate and concentrated at reducedpressure. The residue was triturated with ether to give tan crystals (mp233°-225° C.). Recrystallization from methylene chloride gave creamcolored prisms, mp 224°-225° C.

EXAMPLE 144-Azidomethyl-5-[4-chloro-2-(benzoyl)phenyl]-2H-1,2,3-triazole

A mixture of 5.9 g (16 mmole) of3-benzoyloxy-1-[4-chloro-2-(benzoyl)phenyl]propyne, 5.2 g (80 mmole) ofsodium azide and 210 ml of N,N-dimethylformamide was heated in an oilbath to 80°-90° C. for 30 hr. After cooling, the mixture was poured into520 ml of ice water and extracted with methylene chloride. The methylenechloride solution was washed with water, dried with anhydrous sodiumsulfate, and concentrated at reduced pressure. The residual oil wascrystallized from a mixture of methylene chloride and hexane to givelight tan crystals. Recrystallization from a mixture of methylenechloride and hexane gave off-white crystals, mp 128°-131° C.

EXAMPLE 15 8-Chloro-6-phenyl-2H,4H-[1,2,3]triazolo[4,5-d][2]benzazepine

A mixture of 3 g (8.9 mmole) of4-azidomethyl-5-[4-chloro-2-(benzoyl)phenyl]-2H1,2,3-triazole and about3 teaspoonsful of Raney nickel in 150 ml of ethanol was shaken in a Parrbottle with an initial hydrogen pressure of 5 p.s.i. for 1 hr. Thecatalyst was removed by filtration and the filtrate was concentrated atreduced pressure to give 2 g of gummy solid. The residue waschromatographed over silica gel using a 1:1 mixture of ethyl acetate andmethylene chloride as eluent. Evaporation of the solvent gave a gumwhich crystallized from a small amount of ethyl acetate to give whitecrystals. Recrystallization from a mixture of ethyl acetate andpetroleum ether gave colorless prisms, mp 203°-205° C.

EXAMPLE 16 5-Chloro-2-iodobenzophenone

A mixture of 76 g (1.1 mole) of sodium nitrite and 450 ml of sulfuricacid was heated on a steam bath to ca 80° until complete solution wasachieved. The solution was cooled to 30° and 232 g (1.0 mole) of2-amino-5-chlorobenzophenone was added in portions keeping thetemperature between 30° and 40°. The mixture was stirred for 1 hr andthen slowly poured into 3 L of an ice and water mixture. The solutionwas filtered through Hy-Flo and to the stirred filtrate was added slowlya solution of 200 g (1.83 mole) of sodium fluoborate in 800 ml of water.The resulting precipitate was collected by filtration and washed withwater (2×100 ml) to give a moist white solid.

The moist 2-benzoyl-4-chlorobenzenediazonium fluoborate was slurried in3 L of water, and a solution of 332 g (2 moles) of potassium iodide in 1L of water was added dropwise. The mixture was stirred at roomtemperature for 4 hr and the resulting precipitate was collected byfiltration. The crude product was added to 1 L of boiling ether,filtered, and dried with anhydrous sodium sulfate. The ether solutionwas concentrated to 500 ml and the addition of 100 ml of petroleum ethergave end product. A small amount of end product was recrystallized froma mixture of ether and petroleum ether to give light yellow prisms, mp80°-82°.

EXAMPLE 17 5-Chloro-2'-fluoro-2-iodobenzophenone

The preparation of 5-chloro-2'-fluoro-2-iodobenzophenone was conductedin the same manner as the preparation of 5-chloro-2-iodobenzophenone togive the end product as light yellow prisms, mp 78°-81°.

EXAMPLE 18 2',5-Dichloro-2-iodobenzophenone

The preparation of 2'-5-dichloro-2-iodobenzophenone was conducted in thesame manner as the preparation of 5-chloro-2-iodobenzophenone to givethe end product as light yellow prisms, mp 64°-66°.

EXAMPLE 19 2-Iodobenzophenone

The preparation of 2-iodobenzophenone was conducted in the same manneras the preparation of 5-chloro-2-iodobenzophenone to give the endproduct as a brown oil. A small amount was purified by columnchromatography to give the end product as white prisms, mp 29°-31°.

EXAMPLE 20 2'-Chloro-2-iodobenzophenone

The preparation of 2'-chloro-2-iodobenzophenone was conducted in thesame manner as the preparation of 5-chloro-2-iodobenzophenone to givethe end product as pale yellow prisms, mp 62°-64°.

EXAMPLE 21 1-[4-Chloro-2-benzoylphenyl]-3-phthalimidopropyne

A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole)of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g(0.20 mole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and400 ml of methylene chloride was stirred at room temperature under argonuntil complete solution was obtained. In one portion, 40.0 g (0.22 mole)of N-propargylphthalimide was added to the solution and the resultingmixture stirred for 20 hr. The volatiles were removed at reducedpressure and the residue was triturated with 200 ml of iospropanol. Theresulting percipitate was collected by filtration to give crude endproduct. Recrystallization from acetone gave cream colored prisms, mp148°-150° C.

EXAMPLE 22 1-[4-Chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne

The preparation of1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopyropyne wasconducted in a similar manner as the preparation of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne to give cream coloredprisms, mp 158°-161° C.

EXAMPLE 23 1-[4-Chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne

The preparation of1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne wasconducted in the same manner as the preparation of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne to give cream coloredprisms, mp 144°-145° C.

EXAMPLE 24 1-[2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne

The preparation of 1-[2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropynewas conducted in the same manner as the preparation of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne to give cream coloredprisms, mp 149°-150° C.

EXAMPLE 25 1-[2-benzoylphenyl]-3-phthalimidopropyne

The preparation of 1-[2-benzoylphenyl]-3-phthalimidopropyne wasconducted in the same manner as the preparation of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne to give cream coloredprisms, mp 164°-165° C.

EXAMPLE 268-Chloro-6-(2-fluorophenyl)-2-methyl-2H,4H-[1,2,3]triazolo[3,4-d][2]benzazepine(A) and8-Chloro-6-(2-fluorophenyl)-3-methyl-2H,4H-[1,2,3]triazolo[3,4-d][2]benzazepine(B)

A mixture of 2.6 g (9.4 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-[1,2,3]triazolo[3,4-d][2]benzazepine,2.0 mL (21 mmol) of dimethylsulfate and 10 mL of 3 N aqueous sodiumhydroxide in 25 mL of ethanol was stirred at room temperature for 5 hr.The mixture was diluted with water, neutralized with 1 N hydrochloricacid, and extracted with methylene chloride. The methylene chloridesolution was washed with water, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to give a yellow oil. Purification bycolumn chromatography (silica gel, 35 g; ethyl acetate eluent) gave asthe major component A as a foam. Crystallization from a mixture of etherand petroleum ether gave A as colorless crystals, mp 105°-107° C.assigned to be the 2-position isomer.

A later fraction gave a colorless oil which when treated with 2 mL of 1M methanolic methanesulfonic acid gave B as fine yellow needles, mp255°-257° C. assigned to the 3-position isomer.

EXAMPLE 27 5-Chloro-2'-fluoro-2-iodobenzhydrol

A mixture of 54 g (0.15 mole) of 5-chloro-2'-fluoro-2-iodobenzophenoneand 28.4 g (0.75 mole) of sodium borohydride in 1000 ml of ethanol wasstirred at 0° C. for 15 min. The solution was diluted with water andextracted with ether. The ether solution was washed with water, driedover anhydrous sodium sulfate, and concentrated at reduced pressure togive a deep yellow oil.

EXAMPLE 281-{4-Chloro-2-[(2-fluorophenyl)hydroxymethyl]-phenyl}-3-phthalimidopropyne

The preparation of1-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-3-phthalimidopropynewas conducted in the same manner as the preparation of1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne to give pale yellowprisms, mp 158°-160° C.

EXAMPLE 29

    ______________________________________                                        TABLET FORMULATION (Wet granulation)                                                              mg/     mg/   mg/   mg/                                   Item Ingredients    tablet  tablet                                                                              tablet                                                                              tablet                                ______________________________________                                        1.   8-chloro-6-(2-chloro-                                                                         1       5    10    25                                         phenyl)-2H, 4H-                                                               [1,2,3]triazolo[4,5-d]                                                        [2]benzazepine                                                                8-chloro-6-phenyl-                                                            2H, 4H-[1,2,3]triazolo                                                        [4,5-d][2]benzazepine                                                    2.   Lactose        202     232   261   280                                   3.   Modified Starch                                                                              25      35    45    55                                    4.   Pregelatinized Starch                                                                        20      25    30    35                                    5.   Distilled Water q.s.                                                                         --      --    --    --                                    6.   Magnesium Stearate                                                                            2       3     4     5                                                        --      --    --    --                                         Weight of tablet                                                                             250 mg  300 mg                                                                              350 mg                                                                              400 mg                                ______________________________________                                    

Procedure:

1. Mix Items 1-4 in a suitable mixer.

2. Granulate with sufficient distilled water to proper consistency.Mill.

3. Dry in a suitable oven.

4. Mill and mix with magnesium stearate for 3 minutes.

5. Compress on a suitable press equipped with appropriate punches.

EXAMPLE 30

    ______________________________________                                        TABLET FORMULATION (Direct compression)                                                           mg/     mg/   mg/   mg/                                   Item Ingredients    tablet  tablet                                                                              tablet                                                                              tablet                                ______________________________________                                        1.   8-chloro-6-(2-chloro-                                                                         1       5    10    25                                         phenyl)-2H, 4H-                                                               [1,2,3]triazolo[4,5-d]                                                        [2]benzazepine                                                                8-chloro-6-phenyl-                                                            2H, 4H-[1,2,3]triazolo                                                        [4,5-d][2]benzazepine                                                    2.   Lactose        221     217   212   181                                   3.   Avicel         45      45    45    55                                    4.   Direct Compression Starch                                                                    30      30    30    35                                    5.   Magnesium Stearate                                                                            3       3     3     4                                                        --      --    --    --                                         Weight of tablet                                                                             300 mg  300 mg                                                                              300 mg                                                                              300 mg                                ______________________________________                                    

Procedure:

1. Mix Item 1 with an equal amount of lactose. Mix well.

2. Mix with Items 3, and 4, and the remaining amount of Item 2. Mixwell.

3. Add magnesium stearate and mix for 3 minutes.

4. Compress on a suitable press equipped with appropriate punches.

EXAMPLE 31

    ______________________________________                                        CAPSULE FORMULATION                                                                               mg/     mg/   mg/   mg/                                   Item Ingredients    tablet  tablet                                                                              tablet                                                                              table                                 ______________________________________                                        1.   8-chloro-6-(2-chloro-                                                                         1      5     10    25                                         phenyl)-2H,4H-                                                                [1,2,3]triazolo[4,5-d]                                                        [2]benzazepine                                                                8-chloro-6-phenyl-                                                            2H,4H-[1,2,3]triazolo                                                         [4,5-d][2]benzazepine                                                    2.   Lactose        203     293.5 328   372.5                                 3.   Starch         30      35    40    30                                    4.   Talc           15      15    20    20                                    5.   Aerosol OT      1      1.5   2     2.5                                                       --      --    --    --                                         Capsule fill weight                                                                          250 mg  350 mg                                                                              400 mg                                                                              450 mg                                ______________________________________                                    

Procedure:

1. Mill Items 1, 2, 3, and 5 in a suitable mixer. Mill.

2. Add talc and mix well.

3. Encapsulate on suitable equipment.

What is claimed:
 1. A compound of formula ##STR6## wherein X and Y arehydrogen or halogen.